Since its recognition in 1981, the acquired immunodeficiency syndrome (AIDS) has become a major pandemic. The worldwide prevalence of HIV infection has been, estimated at more than 18,500,000 cases, with an additional estimate of 1.5 million infected children (R. Famighetti, 1996 World Almanac and Book of Facts, World Almanac Books, Mahwah, N.J., [1995], p. 840).
The etiologic agent associated with AIDS was identified as the human immunodeficiency virus (HIV). HIV is classified as a retrovirus, as it contains reverse transcriptase (RT), a multi-functional enzyme that contains RNA-dependent DNA polymerase activity, as well as DNA-dependent DNA polymerase and ribonuclease H activities. These three activities are essential for the conversion of genomic retroviral RNA into double-stranded DNA that can then be integrated into an infected host cell genome.
HIV is a D-type virus within the lentivirus family, with two major antigenic types (HIV-1 and HIV-2). HIV-1 and HIV-2 share approximately 40% genetic identity, although they can be readily distinguished based on differences in antibody reactivity to the envelope glycoprotein (M. Cloyd, “Human Retroviruses,” in S. Baron (ed.), Medical Microbiology, University of Texas Medical Branch at Galveston, [1996], pp. 761-775). Both HIV-1 and HIV-2 have been associated with AIDS.
The search for effective drugs against HIV has focused on targeting various critical components of the replication cycle of HIV-1. One important component in this cycle is the reverse transcriptase enzyme. Indeed, perhaps because of its pivotal role in the life cycle of HIV, it was the target of the first clinically approved anti-retroviral agents (see, Patel et al., “Insights into DNA Polymerization Mechanisms from Structure and Function Analysis of HIV-1 Reverse Transcriptase,” Biochem., 34:5351-5363 [1995]), although other compounds such as protease inhibitors have recently been introduced. In addition to its critical role in HIV replication, targeting RT has a potential benefit in reducing the toxicity to the patient associated with many drugs, as human cells do not normally contain this RT activity. Therefore, the potential for targeted inhibition of only viral replication and not host cell multiplication is present. However, this potential has yet to be realized.
There are two major classes of RT inhibitors. The first comprises nucleoside analogues, such as 3′-azido-3′-deoxythymidine (AZT), 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), and 2′,3′-dideoxycytidine (ddC). These compounds are analogs of normal deoxynucleoside triphosphates (dNTPs). However, these are not specific for HIV RT, and are incorporated into cellular DNA by host DNA polymerases; thus, these compounds can cause serious side effects. Moreover, administration of these analogs has resulted in the emergence of drug-resistant viral strains that contain mutations in their RT. Thus, these RT inhibitors have dangers that must be considered in developing treatment regimens for HIV-infected patients.
The second major class of RT inhibitors comprises the non-nucleoside RT inhibitors (NNRTI), such as tetrahydroimidazo(4,5,1-1-jk)(1,4)-benzodiazepin-2-(1H)-one, and -thione (TIBO) derivatives, dipyridodiazepinones, pyridinones, bis(heteroaryl)piperazines (BHAPs), 2′,5′-bis-O-(tertbutyldimethylsilyl)-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide)pyrimidine (TSAO) derivatives, α-anilinophenylacetamide (α-APA), 8-chloro-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepine-2 (1H)-one (8-Cl TIBO), and nevirapine. (See, e.g., Pauwels et al., “Potent and Selective Inhibition of HIV-1 Replication in Vitro By a Novel Series of TIBO Derivatives,” Nature 343:470-474 [1990]; Merluzzi et al., “Inhibition of HIV-1 Replication by a Non-Nucleoside Reverse Transcriptase Inhibitor,” Science 250:1411-1413 [1990]; Goldman and Stern, “Pyridinone Derivatives: Specific Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitors with Antiviral Activity,” Proc. Natl. Acad. Sci. USA 88:6863-6867 [1991]; Romero and Tarpley, “Non-Nucleoside Reverse Transcriptase Inhibitors that Potently and Specifically Block Human Immunodeficiency Virus Type 1 Replication,” Proc. Natl. Acad. Sci., USA 88:8806-8810 [1991]; Balzarini et al., “2′,3′-Bis-O-(Tertbutyldimethylsilyl)-3′-Spiro-5″-(4″-Amino-1″,2″-Oxathiole-2″,2″-Dioxide) Pyrimidine (TSAO) Nucleoside Analogs: Highly Selective Inhibitors of Human Immunodeficiency Virus Type 1 That are Targeted at the Viral Reverse Transcriptase,” Proc. Natl. Acad. Sci. USA 89:4392-4396 [1992]; Young, “Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase,” Perspect. Drug Discov. Des., 1:181-192; and Pauwels et al., “Potent and Highly Selective Human Immunodeficiency Virus Type 1 (HIV-1) Inhibition by a Series of α-Anilinophenylacetamide Derivatives Targeted at HIV-1 Reverse Transcriptase,” Proc. Natl. Acad. Sci., USA 90:1711-1715 [1993]).
Unlike the nucleoside analogues, the NNRTIs do not act as chain terminators and do not bind at the dNTP-binding site. The majority of these compounds have been shown to share a common binding site unique to HIV-1 RT that is located in proximity to the RT polymerase active site. (See, Tantillo et al., “Locations of Anti-AIDS Drug Binding Sites and Resistance Mutations in Three-Dimensional Structure of HIV-1 Reverse Transcriptase. Implications for Mechanisms of Drug Inhibition and Resistance,” J. Mol. Biol., 243:369-387 [1994]; Smith et al., “Molecular Modeling Studies of HIV-1 Reverse Transcriptase Nonnucleoside Inhibitors: Total Energy of Complexation as a Predictor of Drug Placement and Activity,” Prot. Sci., 4:2203-2222 [1995]; Ding et al., “Structure of HIV-1 TR/TIBO R86183 Complex Reveals Remarkable Similarity in the Binding of Diverse Nonnucleoside Inhibitors,” Nature Struct. Biol., 2:407-415 [1995]; and Nanni et al., “Review of HIV-1 Reverse Transcriptase Three Dimensional Structure: Implications for Drug Design,” Perspect. Drug Discov. Des., 1:129-150 [1993]).
NNRTIs are highly specific for HIV-1 RT, and do not inhibit either HIV-2 RT or normal cellular polymerases, resulting in lower cytotoxicity and fewer side effects than the nucleoside analogs. (See, e.g., Ding et al., “Structure of HIV-1 Reverse Transcriptase in a Complex with the Non-Nucleoside Inhibitor α-APA R 95845 at 2.8 Å Resolution,” Structure 3:365-379 [1995]). However, resistance to some of these compounds has been reported. (See, e.g., Nunberg et al., “Viral Resistance to Human Immunodeficiency Virus Type 1-Specific Pyridinone Reverse Transcriptase Inhibitors,” J. Virol., 65:4887-4892 [1991]; Tantillo et al., “Locations of Anti-AIDS Drug Binding Sites and Resistance Mutations in the Three-Dimensional Structure of HIV-1 Reverse Transcriptase: Implications for Mechanisms of Drug Inhibition and Resistance,” J. Mol. Biol., 243:369-387; and Richman, “Resistance of Clinical Isolates of Human Immunodeficiency Virus to Antiretroviral Agents,” Antimicrob. Agents Chemother., 37:1207-1213 [1993]).
Despite recent developments in drug and compound design to combat HIV, there remains a need for a potent, non-toxic compound that is effective against wild type (WT) RTs, as well as RTs that have undergone mutations, and thereby become refractory to commonly used anti-HIV compounds.